The pathogenesis and severity of hepatitis B virus (HBV) infection may be determined to a great extent by the cellular proteins to which it or its components bind. In addition, interactions between HBV and the p53 gene may play a role in determining the nature of the outcome of the infection. In order to study the mechanisms by which p53 function is regulated (in the context of HBV-associated HCC), human wild-type p53 cDNA was cloned into a vaccinia virus vector and the expressed p53 protein was used to investigate binding of the p53 by cellular proteins from a cDNA expression library from a human liver. One protein that bound wild-type p53 had >99% homology with DNA topoisomerase IIb. Hepatocellular carcinomas (HCCs) and adjacent nontumorous liver tissues were studied to determine the level of expression of topoisomerase II and p53. Overexpressed topoisomerase II proteins were detected by western blot in six of ten HCCs from China (60%) and 15/20 HCCs from Japan (75%), including some in which presumed wild-type p53 was detected by immunohistochemistry. No topoisomerase II expression was detectable in nontumorous liver tissues from the same patients or in a sample of normal human liver from a patient who died of other causes.